Gómez-Garre D, Largo R, Tejera N, Fortes J, Manzarbeitia F, Egido J
Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Hypertension. 2001 Apr;37(4):1171-8. doi: 10.1161/01.hyp.37.4.1171.
The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-kappaB (NF-kappaB), which regulates the transcription of many genes involved in renal injury, could be implicated. In rats with intense proteinuria, we studied the renal activation of NF-kappaB as well as the potential involvement of the vasoactive hormones angiotensin II (Ang II) and endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1 g/d of BSA had proteinuria but no renal morphological lesions at day 1. By contrast, tubular atrophy and/or dilation and mononuclear cell infiltration were observed after 8 or 28 days of BSA administration, coinciding with maximal proteinuria. In relation to control uninephrectomized rats, the renal cortex of nephritic rats showed an increment in the activation of NF-kappaB at all time periods studied. By in situ Southwestern histochemistry, NF-kappaB activity was mainly localized in proximal tubules, interstitial mononuclear cells, and, to a lesser extent, the glomeruli. The administration of the ACE inhibitor quinapril plus the ET(A)/ET(B) receptor antagonist bosentan during 28 days to BSA-overloaded animals diminished proteinuria, renal lesions, and NF-kappaB activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-kappaB activation in a time- and dose-dependent manner. Incubation of cells with receptor antagonists of Ang II (AT(1): losartan and AT(2): PD-123,319) or ET-1 (ET(A): BQ123 and ET(B): IRL1038) inhibited significantly the BSA-induced NF-kappaB activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-kappaB activation in tubular epithelial cells both in vivo and in vitro. The vasoactive peptides Ang II and ET-1 appear to be implicated in this effect. The results reveal a novel mechanism of perpetuation of renal damage induced by persistent proteinuria.
持续性蛋白尿诱发间质炎症和纤维化的机制尚不清楚，尽管可涉及调节许多参与肾损伤基因转录的核因子-κB（NF-κB）。在蛋白尿严重的大鼠中，我们研究了NF-κB的肾内激活以及血管活性激素血管紧张素II（Ang II）和内皮素-1（ET-1）的潜在作用。接受1g/d牛血清白蛋白（BSA）的单侧肾切除Wistar-Kyoto大鼠在第1天时出现蛋白尿，但无肾脏形态学损伤。相比之下，在给予BSA 8天或28天后观察到肾小管萎缩和/或扩张以及单核细胞浸润，这与最大蛋白尿期一致。与对照单侧肾切除大鼠相比，在所有研究时间段内，肾炎大鼠的肾皮质NF-κB激活均增加。通过原位西南组织化学分析，NF-κB活性主要定位于近端小管、间质单核细胞，在较小程度上定位于肾小球。在28天内给BSA负荷动物给予血管紧张素转换酶（ACE）抑制剂喹那普利加ET(A)/ET(B)受体拮抗剂波生坦，比单一药物更显著地减少蛋白尿、肾脏损伤和NF-κB活性。暴露于BSA的培养肾小管上皮细胞显示出强烈的NF-κB激活，呈时间和剂量依赖性。用Ang II受体拮抗剂（AT(1)：氯沙坦和AT(2)：PD-123,319）或ET-1受体拮抗剂（ET(A)：BQ123和ET(B)：IRL1038）孵育细胞可显著抑制BSA诱导的NF-κB活性（分别相对于基础水平抑制90%、75%、90%和60%）。我们的结果表明，超负荷蛋白尿在体内和体外均可导致肾小管上皮细胞中NF-κB激活。血管活性肽Ang II和ET-1似乎参与了这一效应。这些结果揭示了持续性蛋白尿诱导肾损伤持续存在的一种新机制。
